Azologization of serotonin 5-HT3 receptor antagonists

Article abstract of DOI:10.3762/bjoc.15.74

The serotonin 5-hydroxytryptamine 3 receptor (5-HT₃R) plays a unique role within the seven classes of the serotonin receptor family, as it represents the only ionotropic receptor, while the other six members are G protein-coupled receptors (GPCRs). The 5-HT₃ receptor is related to chemo-/radiotherapy provoked emesis and dysfunction leads to neurodevelopmental disorders and psychopathologies. Since the development of the first serotonin receptor antagonist in the early 1990s, the range of highly selective and potent drugs expanded based on various chemical structures. Nevertheless, on-off-targeting of a pharmacophore’s activity with high spatiotemporal resolution as provided by photopharmacology remains an unsolved challenge bearing additionally the opportunity for detailed receptor examination. In the presented work, we summarize the synthesis, photochromic properties and in vitro characterization of azobenzene-based photochromic derivatives of published 5-HT₃R antagonists. Despite reported proof of principle of direct azologization, only one of the investigated derivatives showed antagonistic activity lacking isomer specificity.

Full text of DOI:10.3762/bjoc.15.74

Azologization of serotonin 5-HT3 receptor antagonists
Karin Rustler1, Galyna Maleeva2, Piotr Bregestovski2,3,4 and Burkhard König*1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2019, 15, 780–788.
1Institute of Organic Chemistry, University of Regensburg, 93053
Regensburg, Germany, 2Aix-Marseille University, INSERM, INS,
Institut de Neurosciences des Systèmes, 13005 Marseille, France,
3Department of Normal Physiology, Kazan State Medical University,
Kazan, Russia and 4Institute of Neurosciences, Kazan State Medical
University, Kazan, Russia
doi:10.3762/bjoc.15.74
Received: 28 January 2019
Accepted: 14 March 2019
Published: 25 March 2019
This article is part of the thematic issue "Dyes in modern organic
chemistry".
Email:
Burkhard König* - burkhard.koenig@ur.de
Guest Editor: H. Ihmels
* Corresponding author
© 2019 Rustler et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
azobenzene; 5-HT3R; ion currents; photopharmacology; serotonin
Abstract
The serotonin 5-hydroxytryptamine 3 receptor (5-HT3R) plays a unique role within the seven classes of the serotonin receptor
family, as it represents the only ionotropic receptor, while the other six members are G protein-coupled receptors (GPCRs). The
5-HT3 receptor is related to chemo-/radiotherapy provoked emesis and dysfunction leads to neurodevelopmental disorders and
psychopathologies. Since the development of the first serotonin receptor antagonist in the early 1990s, the range of highly selective
and potent drugs expanded based on various chemical structures. Nevertheless, on-off-targeting of a pharmacophore’s activity with
high spatiotemporal resolution as provided by photopharmacology remains an unsolved challenge bearing additionally the opportu-
nity for detailed receptor examination. In the presented work, we summarize the synthesis, photochromic properties and in vitro
characterization of azobenzene-based photochromic derivatives of published 5-HT3R antagonists. Despite reported proof of prin-
ciple of direct azologization, only one of the investigated derivatives showed antagonistic activity lacking isomer specificity.
Introduction
5-Hydroxytryptamine (5-HT), commonly known as serotonin or enteric nerve depolarization [10]. It is also found in the
[1,2] or enteramine [3,4], is a monoamine neurotransmitter and platelets, where it is presumably involved in blood coagulation
hormone which is produced in the brain and in intestines and and vasoconstriction. Furthermore, serotonin is one of the
regulates a large variety of physiological functions in the first neurotransmitters to appear during development [11] and
mammalian central and peripheral nervous system [1,5]. In the may have an organizing function in the development of
central nervous system (CNS), it modulates sleep–wake cycles, the mammalian CNS being involved in cell division, differ-
emesis, appetite, mood, memory, breathing, cognition and entiation, survival, neuronal migration [12,13] and synapto-
numerous other functions [6-9]. In the gastrointestinal (GI) genesis [14]. Dysfunction of the 5-HT receptor (5-HTR)
tract, it causes peristalsis via either smooth muscle contraction signalling during early developmental stages my lead to altered
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cognitive ability, neurodevelopmental disorders, and increased chemical structure of a known pharmacophore towards a photo-
incidence of psychopathologies such as autism and schizo- chromic moiety or via replacement of certain parts of the bio-
phrenia [15,16].
molecule to generate a photochromic hybrid biomolecule. In
this context, various photochromic scaffolds including
Serotonin operates via seven classes of 5-HT receptors of which dithienylethenes, fulgi(mi)des, and azobenzenes are investigat-
six are G protein-coupled receptors (GPCRs) and only one, the ed [31,42]. The latter ones were already discovered in 1834 by
5-HT3R, is a ligand-gated cation channel [5,6,17]. When this re- E. Mitscherlich [43] but it took around another 100 years till
ceptor was identified and cloned [18-20], it became clear that G. S. Hartley [44] revealed their photo-induced trans–cis
5-HT3 takes a unique position as pentameric ligand-gated isomerization representing the time of birth of the azobenzene
cation-selective ion channel belonging to the Cys-loop receptor photoswitch. Benefiting of their accessible synthesis, large
subfamily. In vertebrates, this family also includes nicotinic change in polarity and geometry upon switching, excellent pho-
acetylcholine receptors (nAChRs), γ-aminobutyric acid type A tochromic properties and tuneability, azobenzenes are amongst
receptors (GABAARs), and glycine receptors (GlyRs). To date, the most widely used photochromic scaffolds [31,42,45-47].
five subunits of the 5-HT3 receptor are identified (5-HT3A–5- Since their first use in a biological environment in the late
HT3E) [21]. Functional receptors are either constructed as 1960s for the photoregulation of the enzymatic activity of
5-HT3A homopentamers or as heteropentamers containing chymotrypsin [48], their applications in biology widely
5-HT3A and 5-HT3B receptor subunits [22-24].
expanded towards receptor control [49-52] and fields as bacteri-
al growth [53], vision restoration [53-55], the respiratory chain
5-HT3 receptors are highly expressed in the brainstem, espe- [56] and lipids [57,58]. Owing to the reported serotonin antago-
cially in areas involved in the vomiting reflex and in the dorsal nists’ chemical structures, the use of azobenzene as photochro-
horn of the spinal cord [25]. These receptors are also expressed mic scaffold in the presented work seemed axiomatic. There-
presynaptically providing regulation of the neurotransmitters fore, the primary design of our photochromic derivatives is
release [21,22].
based on the direct “azologization” [59] of reported non-photo-
chromic antagonists [60,61] via replacement of the benzene-
Besides targeting of 5-HT3Rs for the treatment of psychiatric ring connecting amide bond and thioether, respectively, by an
disorders, they are object to counteract postoperative nausea azo bridge.
and chemo-/radiotherapy provoked emesis [26-29]. In the early
Results and Discussion
1990s, the first potent and selective 5-HT3 receptor antagonist
Design and synthesis of azobenzene-based
photochromic modulators
ondansetron was initially developed [26]. Since then the devel-
opment of 5-HT3R antagonists progressed. The first-generation
antagonists are structurally categorized in three major classes:
(I) carbazole derivatives (e.g., ondansetron), (II) indazoles
(e.g., granisetron), and (III) indoles (e.g., dolasetron) [26,30].
Generally, 5-HT3R antagonists share a basic amine, a rigid
(hetero-)aromatic system and a carbonyl group or isosteric
equivalent which is coplanar to the aromatic system. Although
the antagonists show a general structural motive, they differ in
their binding affinities, dose responses, and side effects [22].
The reported [60,61] scaffolds of 5-HT3R antagonists are based
on an aromatic system either connected to a purine/pyrimidine
moiety via a thioether bridge or a quinoxaline moiety via an
amide bond. Referring to this work performed by the groups of
DiMauro [60] and Jensen [61], we envisioned that the replace-
ment of the thioether or amide bond (Scheme 1) by an azo
bridge would result in highly active photochromic serotonin
5-HTR antagonists controllable by irradiation with light. Based
on the suggested receptor binding mode reported for one potent
non-photochromic antagonist (lead structure of 16c) [61] we ex-
pected the extended trans-isomer as biologically active configu-
ration whereas its bent cis-isomer should be inactive.
To improve prospective antagonists and obtain a systematic tool
for receptor investigation, spatial and temporal restriction of
ligand binding and concomitant activity regulation is desirable.
Fuelled by light, the growing field of photopharmacology
provides a noninvasive method to trigger a drug’s pharmacolog-
Synthesis of the quinoxaline-based
ical response on demand [31-33]. To introduce photorespon- azobenzenes
siveness into a biological system, different approaches are The synthesis of the unsubstituted quinoxaline-based azoben-
feasible, e.g., the use of caged ligands (CL) [34-37], photo- zene derivatives 5a and 5b is based on a Baeyer [62]–Mills [63]
switchable tethered ligands (PTLs) [38-40], photoswitchable or- reaction (Scheme 2). Therefore, nitrosoquinoxaline 3 was
thogonal remotely tethered ligands (PORTLs) [41] or photo- synthesized in a two-step procedure starting from 2-chloro-
chromic ligands (PCLs) [31,42]. The latter ones represent small quinoxaline (1), which was transformed into its oxime 2 using
molecules, which can either be engineered via extension of the hydroxylammonium chloride [64]. The subsequent oxidation
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Scheme 1: Approach of the direct azologization of reported [60,61] serotonin 5-HT3R antagonists via replacement of a thioether or amide bond by an
azo bridge.
Scheme 2: Synthesis of the differently substituted quinoxaline azobenzene derivatives 5a and 5b via Baeyer [62]–Mills [63] reaction [64,65].
was performed using periodic acid as oxidant [65]. The subse- The methoxy-substituted quinoxaline azobenzene derivative
quent reaction with differently substituted anilines in acetic acid 12a was synthesized via a different synthetic route depicted in
[65] provided both quinoxaline azobenzene derivatives in good Scheme 3. In a first step, p-toluidine (4a) was diazotized using
yields.
sodium nitrite and subsequently reacted with the 2-chloroacetyl-
Scheme 3: Synthesis of the methoxy-substituted quinoxaline derivative 12a via diazotization [66-69].
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acetone ester derivative 7 providing hydrazine 8 [66]. Upon of the hydrazine moiety afforded the corresponding azobenzene
reaction of the chloro-ester 8 with phenylenediamine (9) in the derivatives 16a–d [71].
presence of triethylamine the quinoxaline moiety was formed
Synthesis of azobenzene-extended thio-
[67]. Oxidation of the hydrazine derivative 10 using hydrogen
peroxide under an oxygen atmosphere afforded the quinoxaline purine derivatives
azobenzene derivative 11 [68]. Subsequent methylation using To further tune the photochromism and compare the properties
methyl iodide [69] mainly resulted in the formation of the of direct azologization to azo-extension, two additional deriva-
N-methylated non-photochromic product 12b but in low yields tives of the in vitro most promising naphthalene azopurine 16c
also the desired photochromic methoxy-substituted quinoxaline were synthesized either by keeping the original thioether
azobenzene derivative 12a.
(Scheme 5) or replacing it by an amide bond (Scheme 6) known
as common structural feature of 5-HT3R antagonists.
Synthesis of the purine and thienopyrimidine-
based derivatives
Scheme 5 reflects the synthesis of the azo-extended thiomethyl-
Scheme 4 depicts the general procedure applied for the synthe- purine 23 starting with the synthesis of hydroxymethylazoben-
sis of differently substituted purine- and thienopyrimidine zene 19 [72] in a Baeyer [62]–Mills [63] reaction and subse-
azobenzene derivatives. Differently substituted non-photochro- quent nucleophilic substitution using cyanuric chloride (20)
mic antagonists were chosen as lead structures delivering photo- [73] providing chloromethyl azobenzene 21. The introduction
chromic derivatives with varying electronic and thus photochro- of the thiopurine moiety in 23 was accomplished upon reaction
mic properties. The respective arylamines 13a–c were con- of 21 with dihydropurinethione 22 [74].
verted into their corresponding hydrazines 14a–c via di-
azonium-salt formation using sodium nitrite and subsequent The amide-linked derivative of thiomethylpurine azobenzene 23
reduction using tin(II) chloride [70]. The following nucleo- was synthesized via Baeyer [62]–Mills [63] formation of the
philic substitution at a chloro-substituted purine (15a,b) or carboxylated azobenzene 25 starting from aminobenzoic acid
thienopyrimidine (15c), respectively, and subsequent oxidation 24 and nitrosobenzene (18) [75]. Activation using thionyl chlo-
Scheme 4: General procedure for the synthesis of purine- and thienopyrimidine-substituted arylazobenzenes and depiction of the corresponding
structures [70,71].
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Scheme 5: Synthesis of the thiomethyl-linked purine azobenzene 23 [62,63,72-74].
Scheme 6: Synthesis of the amide-linked azobenzene purine 28 [62,63,75-77].
ride [76] afforded the acid chloride 26 and allowed amide-bond absorption at around 450–500 nm in the UV–vis spectrum
formation [77] for the generation of 28 (Scheme 6).
representing the cis-isomer (Figure 1, black arrows). The
absorption bands of the trans and cis-isomers of compounds
12a, 16c, and 16d overlap to such an extent, that no new
Photochromic properties
The investigation of the photochromic properties of the poten- maximum representing the cis-isomer was observed and thus
tial 5-HT3R antagonists 5a, 5b, 12a, 16a–d, 23, and 28 was per- cis–trans isomerization only occurs thermally and is not trigger-
formed in DMSO and depending on their solubility in phos- able by irradiation with visible light. Back-isomerization was
phate buffer + 0.1% DMSO (16a–d) by UV–vis absorption triggered by irradiation with visible light (5a, 5b, 16a, 16b, 23,
spectroscopy. The compounds were dissolved at 50 µM in the and 28) of the indicated wavelength or by thermal relaxation
respective solvent and irradiated with the indicated wave- (5a, 5b, 12a, 16a–d, 23, and 28). The irradiation times were de-
lengths to generate a substantial amount of their cis-isomer. termined by following the UV–vis spectrum upon isomeriza-
This process can be followed by a decrease of the trans-absorp- tion until no more changes in absorption were observed and the
tion maximum at around 350–400 nm and an increase in photostationary state (PSS) was reached. The points of intersec-
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Figure 1: UV–vis absorption spectra measured at 50 µM in DMSO. Left: purine derivative 16c; right: azo-extended derivative 23.
tion in the absorption spectrum upon switching (= isosbestic Patch-clamp studies
points) indicate a clear two-component switching between trans The synthesized azo antagonist derivatives 5a, 5b, 12a, 16a–d,
and cis-species without any degradation or formation of a side- 23, and 28 were tested for their inhibitory activity using the
product (Figure 1, dotted black arrows). The UV–vis absorp- patch-clamp technique on heterologously expressed ionotropic
tion spectra of all compounds are depicted in Supporting Infor- homopentameric 5-HT3A receptors. Only upon addition of 16c
mation File 1, Figures S1–S10 and the data are summarized in the amplitude of the 5-HT3A mediated currents was decreased
Table S1 and Table S2. A comparison of the differently substi- (Figure 2, left). Application of a 50 µM solution of trans-16c in
tuted purine azobenzene derivatives revealed the beneficial its thermal equilibrium decreased the amplitude of 5-HT in-
effect of an o-chloro substitution on the photochromic proper- duced currents on 54 ± 3% (n = 4). However, irradiation-in-
ties of 16b compared to 16c as the electron density at the duced trans–cis isomerization with light of λ = 530 nm and
nitrogen-rich purine core is reduced. Further reduction of the 455 nm, respectively, had no significant effect on the amplitude
electron density was achieved by using a thienopyrimidine of 5-HT3A-mediated currents (Figure 2, right).
(16a) instead of a purine core (16b–d). Nevertheless, the photo-
chromic properties of those heterocyclic, especially purine- Conclusion
based azobenzenes, are rather poor. In addition to direct azo- In the presented work, we address the design, synthesis, photo-
logization, two azo-extended purine derivatives 23 and 28 were chromic characterization and in vitro investigation of in total
synthesized resulting in excellent photochromic properties. nine azobenzene-based derivatives of reported 5-HT3R antago-
Figure 1 compares exemplarily the UV–vis absorption spectra nists. Initially, seven photoligands (5a, 5b, 12a, and 16a–d)
of the naphthalene-azo-purine 16c (left) and its azo-extended either based on quinoxaline (5a, 5b, and 12a) or purine deriva-
azobenzene thioether purine 23 (right). The determination of the tives (16a–d) with varying electronic and thus photochromic
thermal half-lives (THL) of the cis-isomers of compounds 5a, properties were synthesized by direct azologization of the
5b, 12a, 16a–d, 23, and 28 was accomplished by monitoring the respective leads. Especially the purine-based azobenzenes
increase in absorbance which corresponds to the evolution of displayed high solubility in aqueous media. The beneficial
the trans-isomer after irradiation and exposure to dark. In effect of substituents reducing the overall electron density of the
contrast to the heterocyclic compounds 5a, 5b, 12a, and 16a–d purine moiety (16a, 16b) resulted in higher photostationary
with a thermal half-life in the seconds to minutes range, the azo- states and better band separation compared to 16c and 16d.
extended compounds 23 and 28 showed only slow thermal Still, only one compound (16c) showed antagonistic activity in
back-isomerization (day range) at room temperature. Depending patch-clamp studies. This might be explained by the fact that its
on the desired application, both properties may be of benefit. corresponding non-photochromic lead is the inhibitory most
For thermally instable compounds, only one wavelength for active reported [61] antagonist among the investigated ones.
switching is required. In case of thermally stable cis-isomers The partial rigidization of the thioether via incorporation of an
constant irradiation to maintain a substantial amount of the cis- azo bridge might result in a vast loss of activity. Thereby, azo-
isomer can be avoided.
logization of the less potent leads resulted in complete loss of
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Beilstein J. Org. Chem. 2019, 15, 780–788.
Figure 2: On the left panel representative traces of currents induced by the application of 3 µM 5HT (black trace), by 3 µM 5HT and 50 µM trans-16c
(red trace), by 5HT and 16c under constant irradiation (455 nm, blue trace), and again by pure 5HT – wash-out of the studied compound (black trace)
are shown. On the right panel, a graph representing the relative amplitudes of currents in control (black column), at application of trans-16c (red
column), at application of 16c irradiated with blue light (blue column) and at wash-out (gray column) are shown. P > 0.05, paired t-test.
inhibitory activity (5a, 5b, 12a, 16a, 16b, 16d) and only the Acknowledgements
originally most potent derivative 16c kept recordable antago- The authors are grateful for financial support to ERA SynBIO
nistic activity. The missing significant difference in activity grant MODULIGHTOR (PCIN-2015-163-C02-01), the
upon irradiation-induced trans–cis isomerization of 16c is prob- Bundesministerium für Bildung und Forschung (BMBF) and
ably due to its moderate photochromic properties and slow the Russian Science Foundation (grant number: 18-15-00313).
trans–cis isomerization (Figure 1, left). During the patch-clamp We are also grateful to Dr. S. Lummis for kind providing with
analysis, the cells are continuously superfused with external cDNA of 5HT3A subunit. KR thanks Josef Kiermaier and Wolf-
solution resulting in a fast exchange of the surrounding media gang Söllner for mass spectrometry analysis. KR thanks the
and co-applied tested compounds. Thus, the cis-PSS of 16c X-ray department for crystal structure analysis.
might not be reached by irradiation within the short time of
ORCID® iDs
Karin Rustler - https://orcid.org/0000-0001-6548-1333
compound application despite continuous irradiation. Therefore,
two azobenzene-extended derivatives (23 and 28) with im-
Galyna Maleeva - https://orcid.org/0000-0002-1379-1521
proved photochromic properties were synthesized but lost
Piotr Bregestovski - https://orcid.org/0000-0003-2699-7825
antagonistic activity probably due to their increased steric
Burkhard König - https://orcid.org/0000-0002-6131-4850
demand.
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